Complex biological pathways regulate motivated behaviors, such as eating, drinking, and sleeping. Exercise, which can involve intentional planning, or spontaneous interaction, also is a motivated behavior. It is well established that participation in regular exercise is a health benefit for all individuals, yet only 21% of American adults currently meet the federal guidelines for aerobic and muscle strengthening exercise (26). Of the remaining 80%, 25% of American adults report no leisure time physical activity. For youth in grades 9 to 12, the guidelines suggest 60 min of activity per day, and only 27% meet this guideline, with 15% of children reporting no leisure time physical activity at all (26).
Interventions to increase exercise levels among adults have met with modest results, which could be caused by differences in the behavioral intention to exercise. Results from a meta-analysis by Rhodes and de Bruijn showed that 36% of individuals had the intention to exercise but failed to implement that intention, whereas 21% never had any intention to exercise (30). Thus, if this study were extended to the general population, it suggests that, for more than half of people, initiation or maintenance of the motivation to exercise behavior may be flawed. Likewise, in a study of youth aged 10 to 14 yr, self-motivation and intention, as measured through self-administered questionnaires, showed positive correlations with leisure time noncompetitive physical activity (4). In behavioral literature, self-determination theory can provide a theoretical framework for this issue and suggests that extrinsic motivators, such as peer pressure, and external rewards are involved in the initiation of exercise, whereas intrinsic or autonomic motivators, such as enjoyment or health benefits, are involved in maintenance of exercise (6). Both must be used for individuals to meet or exceed the U.S. Centers for Disease Control and Prevention’s recommended guidelines for physical activity. Thus, conscience decisions to engage in and maintain exercise levels must occur. These decisions are innately part of human brain neurophysiology, with biological and molecular correlates.
The brain is the organ of behavior, yet, the biological basis for exercise behavior, especially in the context of autonomic or extrinsic motivation, is not understood fully. In this article a hypothesis for the neurobiological basis of exercise motivation is proposed (Fig. 1). Previous research, mainly using mouse models, has demonstrated clearly a genetic basis for intrinsically motivated exercise and has implicated two neuronal genes — the nescient helix-loop-helix 2 (NHLH2) gene and the dopamine 1A receptor (DRD1A) (22). This article explores how dopamine levels might be controlled through the NHLH2 transcription factor, ultimately controlling the genetic motivation for exercise. We also investigate if polymorphisms in this genetic pathway might account for differences in intrinsic motivation levels among individuals.
NHLH2 AND EXERCISE BEHAVIOR
The NHLH2 gene was identified originally in a homology screen for basic helix-loop-helix genes, and the Nhlh2 knockout mice (N2KO) were described in 1997 as the first neuronal transcription factor knockout mouse with a phenotype of adult-onset obesity (13). The obesity in these animals progresses slowly, beginning to show only after males are at least 12 wk of age or similar to a middle-aged adult (5). Numerous means have been used to show that this line of mice has no overt differences in food intake; rather, reduced exercise levels account for at least part of their slow progression of obesity. Interestingly, N2KO mice show a reduction in both extrinsic (forced; Good, D.J. Unpublished data, 2012) or intrinsic (spontaneous) levels of exercise (5,12).
Although the mouse genetic data for Nhlh2 are quite strong, only one study has linked human NHLH2 polymorphisms to obese phenotypes (1). The single-nucleotide polymorphism (SNP) in human NHLH2 that has been linked to human obesity is nonsynonymous, resulting in a change at position 83 in the NHLH2 protein from alanine to proline (2). This proline is highly conserved throughout NHLH2 orthologs, including DroNSCL in the fruit fly, and in silico analysis demonstrated that the mutation could result in a structural change in the helical region of the basic-helix-loop-helix protein (2). Further analysis of this and other nonsynonymous polymorphisms from the NCBI SNP database (31) yielded five additional NHLH2 SNP that result in amino acid changes in the protein sequence (total, 6) (Table 1), yet none has been linked specifically to human phenotypes.
To date, no studies have linked NHLH2 directly to an exercise phenotype. However, one of the loci, D1S189, listed on the Human Gene Map for Performance and Health-Related Fitness Phenotypes, lies just approximately 300,000 base pairs away from the locus for NHLH2 on chromosome 1p13 (12). D1S189 is linked to a phenotype of exercise-induced tachycardia in one study but, to date, no further studies have identified the gene associated with this marker.
NHLH2 functions as a basic helix-loop-helix transcription factor, and one study has shown its activity to be regulated by lysine acetylation (21). Specifically, NHLH2 acetylation at lysine 49 allows binding of the transcription factor to the promoter of its target gene, resulting in repressed activity/transcription of that gene (21). Western analysis of mouse Nhlh2 proteins yields a pattern of multiple bands, suggestive of multiple posttranslational modifications (data not shown). Using the online in silico analysis tool PAIL (“prediction of acetylation on internal lysines” http://bdmpail.biocuckoo.org/) (20), five additional lysines were found within the NHLH2 sequence (Fig. 2). Using the high stringency algorithm for PAIL, some of these lysines were predicted to have an even higher possibility of acetylation (by score) than the lysine at position 49 (Table 1). When the NHLH2 protein sequence containing one of the five SNP found in the human genome was entered individually into the PAIL program, the predicted acetylation thresholds at some of these lysines were altered, even though the SNP did not directly change the lysines (Table 1). As these SNP polymorphisms are found in the human NHLH2 gene, these data suggest that some SNP can result in altered acetylation of the protein, possibly affecting NHLH2 activity on target genes.
Why does this matter in the context of exercise motivation? A 2011 article by Libert et al. (21) was able to link acetylation status of NHLH2 to expression of the monoamine oxidase A (MAO-A) gene. In brief, deacetylation of NHLH2 by the sirtuin 1 (SIRT1) deacetylase resulted in loss of negative regulation of MAO-A by NHLH2. This group was further able to show that, when NHLH2 was deacetylated, animals were less motivated to explore their environment. Conversely, when NHLH2 was acetylated on the lysine at position 49, it actively bound to the MAO-A promoter and repressed MAO-A expression. In our model, loss of NHLH2 activity, either through deacetylation (by normal SIRT activity), deletion (mouse knockouts), or SNP that affect acetylation, would result in higher transcriptional activity of MAO-A and a predicted increase in sedentary behavior through a reduction of monoamines, including dopamine and serotonin (Fig. 1). Interestingly, none of the known nonsynonymous SNP in NHLH2 affects the lysine at position 49 (Table 1).
MAO-TIVATION AND SEDENTARY BEHAVIOR
MAO-A and the related protein MAO-B catalyze oxidation of monoamine neurotransmitters, resulting in their inactivation. Although both proteins target dopamine, MAO-A shows additional specificity for inactivation of serotonin, norepinephrine, and adrenaline (32). Interestingly, the genes encoding both MAO-A and MAO-B are found adjacent to each other on the X chromosome at Xp11.3 (32). Mice with a targeted deletion of MAO-A have mildly elevated levels of dopamine, with significant increases in serotonin and norepinephrine, and display an altered reaction to stress as well as increased aggression (32). These mouse studies are consistent with what is known about MAO expression and general human behavior (32).
In addition to a regulatory region for binding and transcriptional repression by NHLH2, the MAO-A promoter contains a variable nucleotide tandem repeat (VNTR) polymorphism, which has been studied extensively with regard to impulsivity and aggression. The 3-repeat VNTR results in a low transcriptional activity of the MAO-A gene, whereas those regions with 3.5 or 4 repeats lead to a high transcriptional activity of MAO-A (3). There also are extremely rare variants of 2 and 5 repeats that we did not examine in the current analyses. As increased levels of the MAO-A enzyme would target and degrade monoamines such as serotonin and dopamine, individuals with the 3.5- or 4-repeat VNTR genetic combination might be expected to show depression or lower overall arousal, whereas those with the 3-repeat VNTR for MAO-A might be expected to show more activity in general, which could lead to impulsivity and aggression.
In linking back to NHLH2 and physical exercise, individuals with both the 3.5- or 4-repeat VNTR region, as well as a polymorphism in NHLH2 leading to low acetylation (low repression of MAO-A), would be expected to show the highest levels of MAO-A and sedentary behavior/physical inactivity. Consistent with this, in our model (Fig. 1), exercise could result in a feedback loop, which would act to maintain low MAO-A or high acetylated NHLH2 levels, but this theory has not yet been tested.
Dopaminergic pathways in the central nervous system have been implicated in reward, motivation, motor activity, and emotion, making these pathways ideal targets for the genetic control of intrinsic physical activity motivation. In previous studies, using mainly mouse models, dopamine, or its receptor Drd1, has been implicated in maintaining high physical activity levels (9,22). Mice that show a high spontaneous running wheel activity have significantly lower Drd1 expression than strains of mice with a low running wheel activity, which have a high Drd1 expression (18). In this study, the authors did not see significant differences in levels of other dopamine receptor types when compared between the high and low wheel running strains. These data may suggest that specificity through Drd1 mediates dopaminergic responses for physical activity. It also is known that whole-brain dopamine depletion (19) as well as treatment with dopamine D1R antagonists reduces overall wheel running activity in rodents (29). In rats, intrinsic motivation for running on a motorized treadmill is reduced in rats that have higher postexercise levels of 3,4-dihydroxyphenylacetic acid (DOPAC), which is the MAO-oxidized metabolite of dopamine (28). Interestingly, levels of dopamine and DOPAC are lower in the dorsal raphe nucleus and substantia nigra in mice selected for high running wheel activity (34). Although these data seem to be in opposition of the data presented above, they suggest a regionalization of monoamine levels and actions, which might be controlled via transcriptional regulation of DRD1 and MAO expression levels.
Polymorphisms in the noncoding regions of DRD1 have the potential to affect D1R expression levels. Two SNP, one in each of the 5′ and 3′ untranslated regions of DRD1, show linkage to impulse control disorder (36), and one of these SNP (rs4532) has been found previously in association with motivated alcohol-seeking behavior in alcoholic men (17,23). Furthermore, a study examining SNP in genes that have the potential to change the activity of the dopamine pathway found associations between SNP in two dopamine pathway genes, ACE and SNAP25, for youth who exercised less than 60 min d-1 (35). In addition, the endocannabinoid pathway and, in particular, the cannabinoid receptor-1 (CB1) may be altered in high wheel running mice such that interference in this pathway leads to reduced wheel running (16), and CB1 polymorphisms show linkage to addictive behaviors (24). As the endocannabinoid pathway modulates the dopaminergic pathway (25), this linkage also could be an important mediator of motivated physical activity.
Summary of the Published Evidence for the Hypothesis
Our model (Fig. 1) suggests that individual carriers of SNP that lower either NHLH2 acetylation status or NHLH2 functional activity as a transcriptional modulator or increase MAO-A expression lead to lower active dopamine (or other monoamine) levels and increased sedentary behavior and physical inactivity.
Although the definitive studies have not yet been done, the published evidence from our laboratory and those of others so far clearly supports the hypothesis that polymorphisms in either NHLH2 or MAO-A, especially those that lead to differences in expression or activity level, will be linked to sedentary behavior in humans. The framework of the evidence is as follows:
- Deletion of mouse Nhlh2 gene leads to sedentary behavior, as measured by reduced home cage activity levels when compared with genetically normal mice (12).
- Acetylated NHLH2 negatively regulates the expression of MAO-A gene (21), leading to increased voluntary exercise behavior in rodents.
- SNP in human NHLH2 have the potential to reduce NHLH2 acetylation, which would increase MAO-A gene activity in carriers.
- Variations in the number of repeats in the VNTR region of the MAO-A promoter can modulate the expression of MAO-A.
- Increased MAO-A gene activity leads to lower dopamine levels.
- High dopamine levels or treatment with agents that increase dopamine levels have been linked to higher activity levels (exercise, aggression, reward seeking, etc.) in both humans and in rodent models.
Thus, in this article, the hypothesis that polymorphisms in NHLH2 or MAO-A can be linked genetically to reduced physical activity is put forth and examined.
QUASI-EXPERIMENTAL TESTING OF THE MODEL
To examine human MAO-A genotype and linkage to motivation or obesity, the low-activity 3-repeat VNTR is being compared with the high-activity 4-repeat VNTR using data from the NICHD Study of Early Child Care and Youth Development (SECCYD). According to prior studies summarized above, we hypothesize that a low MAO-A transcriptional activity increases dopamine level, which in turn increases physical activity levels, whereas high MAO-A transcriptional activity would decrease dopamine and physical activity levels.
The SECCYD study recruited 1364 families from 10 sites across the United States and followed children from the first month after birth to age 15 yr. The sample was diverse in terms of socioeconomic status, ethnicity, and geography. The current analysis is based on the subsample of 651 (female, 53.5%) for whom MAO-A information was available. A total of 711 participants provided DNA samples from buccal cheek cells when they were 15 yr old, although the information of MAO-A VNTR was missing for 60 participants.
Physical activity level
Children’s activity level at 54 months old was measured by the mother-reported Activity Level Scale from the Child Behavior Questionnaire (27). The subscale contains 10 items rating on 7-point Likert-type scale (1 = extremely untrue of your child to 7 = extremely true of your child). Mean of the 10 items was computed as children’s score on physical activity level.
For MAO-A, the low transcriptional activity variant has 3 repeats of the VNTR, whereas high transcriptional activity variants have 3.5 or 4 repeats. We recoded low transcriptional activity variants (3/3) as 1 and high transcriptional activity variants (3.5/3.5, 3.5/4, and 4/4) as 0. Heterozygous genotypes for female (18.6% of the sample; 3/3.5 and 3/4) as well as other infrequent variants for MAO-A (3.2%; 2 and 5 repeats) were not included in the current analysis.
Independent-sample T tests were performed to examine the effect of high versus low transcriptional activity MAO-A genotype on children’s physical activity levels. One-tailed P value is applied to all the t tests because a directional hypothesis was made about the effect. Means and error bars are shown in Figure 3. The results revealed that, for the whole sample, the high transcriptional activity MAO-A group showed a significant lower physical activity level than low transcriptional activity peers (t453 = 1.67, one-tailed P = 0.047). Because MAO-A is located on the X-chromosome, we were curious whether sex would moderate the effects of MAO-A genotype on physical activity level. Two-way analysis of variance was conducted, and the interaction between sex and genotype on physical activity level was significant (F1 = 4.26, two-tailed P < 0.04). Therefore, females and males were reexamined separately, and the results showed a salient sex difference. For boys, the two major genotypes for MAO-A did not differ significantly in their association with activity level (t260 = −0.19, one-tailed P = 0.43), whereas, in girls, high transcriptional activity variants showed significantly lower levels of physical activity compared with the low transcriptional activity variant group (t191 = 2.67, one-tailed P < 0.01). The significant difference found for the whole sample was accounted for entirely by the females in the sample.
Using the 651 individual samples from the SECCYD study, without regard to sex, socioeconomic status, body weight, or other possible variables in the study sample, a significant association was found between VNTR genotype and children’s activity level, as rated by their parent. These data support part of our hypothesis that NHLH2 or MAO-A genotype is associated with sedentary behavior. Specifically, individual carriers of a MAO-A VNTR genotype that leads to a high transcriptional activity of MAO-A, and would be predictive to result in lower dopamine levels, showed lower overall parent-reported activity levels than the low-transcriptional activity MAO-A VNTR genotype. Interestingly, when the effects were separated by sex, only the female cohort with a high-transcriptional activity MAO-A showed the activity level association.
High– and low–transcriptional activity alleles of MAO-A have associated differences in antisocial behavior, which in most cases seem to be modified by childhood environment (3). Generally (with some exceptions), increased aggression, impulsivity, panic disorder, attention deficit syndrome, and other forms of negative behavior were present in carriers of the low-transcriptional activity allele only when the individual’s childhood environment was not optimal, such as in the case of child abuse or poor parental care (3). However, these associations were lost in subjects with “good” (by various measures) childhood environments, suggesting on the flip side, that the low-activity alleles of MAO-A in individuals not exposed to childhood adversity or maltreatment might predict normal motivated behavior and possibly positive intrinsic motivation for healthy behaviors such as exercise. One study directly addressed the question of whether an association could be found between personality traits and MAO-A genotype. In 322 staff and medical students recruited from a hospital setting, high-transcriptional activity alleles of MAO-A were correlated significantly with novelty seeking and reward dependence in personality scores, without regard to age or sex of the individuals (33). These data fit with our hypothesis that high-transcriptional activity allele carriers would show a lower intrinsic motivation for exercise and perhaps need more extrinsic rewards.
The significant association with females in our study is interesting on several levels. First, MAO-A is found on the X-chromosome, but a recent review stated that it is still unclear how expression of MAO-A is affected by random inactivation of one X-chromosome in females (3). Some studies have suggested that female carriers of the low-expression alleles are reduced slightly in terms of aggression or antisocial behavior (3). Thus, one could predict from these data that carriers of the low-transcriptional activity MAO-A alleles would show greater intrinsic motivation and greater motivation for healthy behaviors such as regular exercise.
Although we did not examine body weight in the SECCYD study, one study did examine MAO-A genotype and gestational weight gain. In direct support of our hypothesis, high-activity MAO-A allele carriers gained the highest amount of weight during pregnancy (11). However, another study examining body mass index interaction with MAO-A genotype found an association between obesity and the low activity MAO-A allele (7), suggesting that much more work needs to be done to hone in on the differences between these two studies on body weight, especially with respect to whether MAO-A genotype influences positive health behaviors that prevent overweight and obesity.
Variations in human DNA sequence can affect how individuals behaviorally respond to the environment, drugs, hormones, or other encountered influences. SNP are present at a frequency of approximately 0.1% when comparing any two humans with each other (15), whereas there are more than 7000 mapped VNTR in the human genome (10). These variations account for at least some of what makes each of us individually unique. The identification of gene alleles that definitively influence behavior is still in its infancy, especially with regard to the influence of genes on the motivation for increased exercise behavior. The hypothesis put forth and tested herein links the fields of psychology, genomics, and exercise science, serving as a model to direct future studies that can examine whether variations in exercise behavior among individuals can be explained by variations in gene alleles along a single neural pathway, namely, the SIRT → NHLH2 → MAO-A → dopamine → dopamine receptor (DRD1) → exercise level.
In proposing the hypothesis that polymorphisms in NHLH2 or MAO-A can be linked to reduced physical activity, we do not want to imply that changes in other dopaminergic system components, such as the D2-D5 receptors, and tyrosine hydroxylase enzyme levels, or even other neurotransmitter and neuropeptide pathways, are not involved in the neuroadaptation to exercise. In fact, several studies have concluded that the endocannabinoid, hypothalamic-pituitary-adrenal stress response axis, other neuropeptides, as well as some of the other dopamine receptors are modulated in response to exercise or may affect levels of physical activity behavior measured by various means (8,9,14).
In the current article, only MAO-A allele status was tested. The results, however, provide strong support for the hypothesis and justification to further test other genes, including NHLH2, in this pathway, using large cohorts where physical activity, allele status, body weight, and other comodifiers have been measured.
This work for the human study data (from the NICHD Study of Early Child Care and Youth Development or SECCYD) was supported in part by grant HD25451 from the National Institute of Child Health and Human Development (to Deater-Deckard’s colleague Kathleen McCartney).
DNA extraction and genotyping was performed at the Genome Core Facility in the Huck Institutes for Life Sciences at Pennsylvania State University under the direction of Dr. Deborah S. Grove, Director for Genetic Analysis. The authors thank Daniel Berry (University of Illinois) for his many contributions to the genotyping work in the SECCYD. Also, this research would not have been possible without the inspired work of the NICHD Early Child Care Research Network and research staff, who designed and conducted the overall study, or without the dedicated children, families, and teachers who participated in the human study nor the animals and animal care technicians who participated in the animal research. The authors thank Mr. James Foley for his contributions as a summer undergraduate researcher with Drs. Good and Deater-Deckard. The authors also thank Ms. Crystal Farris for graphic design of Figures 1 and 2.
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